NM_024675.4(PALB2):c.1383T>A (p.Ser461Arg) AND Familial cancer of breast

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 12, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000470251.14

Allele description [Variation Report for NM_024675.4(PALB2):c.1383T>A (p.Ser461Arg)]

NM_024675.4(PALB2):c.1383T>A (p.Ser461Arg)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.1383T>A (p.Ser461Arg)

HGVS:

NC_000016.10:g.23635163A>T
NG_007406.1:g.11195T>A
NM_024675.4:c.1383T>AMANE SELECT
NP_078951.2:p.Ser461Arg
NP_078951.2:p.Ser461Arg
LRG_308t1:c.1383T>A
LRG_308:g.11195T>A
LRG_308p1:p.Ser461Arg
NC_000016.9:g.23646484A>T
NM_024675.3:c.1383T>A

Protein change:

S461R

Links:

dbSNP: rs768482110

NCBI 1000 Genomes Browser:

rs768482110

Molecular consequence:

NM_024675.4:c.1383T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000550600	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 12, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26689913, 28492532
SCV004202633	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 26, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000550600

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 12, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004202633

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 26, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000550600.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 461 of the PALB2 protein (p.Ser461Arg). This variant is present in population databases (rs768482110, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 410105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004202633.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine